The present invention relates to inhibitors of the enzyme 11-beta-hydroxysteroid dehydrogenase Type I (11xcex2-HSD-1 or HSD-1), and methods of treatment using such compounds. The compounds are useful for the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions.
Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, the hormone which regulates glucose utilization, and type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein patients produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically treated with exogenous insulin administered via injection. However, type 2 diabetics often develop xe2x80x9cinsulin resistancexe2x80x9d, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia.
Insulin resistance is primarily due to a receptor binding defect that is not yet completely understood. Resistance to insulin results in insufficient activation of glucose uptake, diminished oxidation of glucose and storage of glycogen in muscle, inadequate insulin repression of lipolysis in adipose tissue and inadequate glucose production and secretion by the liver.
Persistent or uncontrolled hyperglycemia that occurs in diabetics is associated with increased morbidity and premature and mortality. Abnormal glucose homeostasis is also associated both directly and indirectly with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Type 2 diabetics are at increased risk of cardiovascular complications, e.g., atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
Many patients who have insulin resistance but have not developed type 2 diabetes are also at a risk of developing symptoms referred to as xe2x80x9cSyndrome Xxe2x80x9d, or the xe2x80x9cmetabolic syndromexe2x80x9d. Syndrome X is characterized by insulin resistance, along with abdominal obesity, hyperinsulinemia, high blood pressure, low HDL and high VLDL. These patients, whether or not they develop overt diabetes mellitus, are at increased risk of developing the cardiovascular complications listed above.
Treatment of type 2 diabetes typically includes physical exercise and dieting. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic xcex2-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistant tissues. However, dangerously low levels of plasma glucose can result, and an increased level of insulin resistance can ultimately occur.
Biguanides increase insulin sensitivity, resulting in some correction of hyperglycemia. However, many biguanides, e.g., phenformin and metformin, cause lactic acidosis, nausea and diarrhea.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) form a newer class of compounds with the potential for ameliorating hyperglycemia and other symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue, resulting in partial or complete correction of the elevated plasma levels of glucose substantially without causing hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR) gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being developed for treatment of Type 2 diabetes and/or dyslipidemia are agonists of one or more of the PPAR alpha, gamma and delta subtypes.
There is a continuing need for new methods of treating diabetes and related conditions. The present invention meets this and other needs.
The present invention relates to a compound represented by Formula I: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A and B may be taken separately or together;
when taken separately,
A represents halo, C1-6alkyl, OC1-6alkyl or phenyl, said alkyl, phenyl and the alkyl portion of OC1-6alkyl being optionally substituted with 1-3 halo groups; and
B represents represents H, halo, C1-6alkyl, xe2x80x94OC1-6alkyl, xe2x80x94SC1-6alkyl, C2-6alkenyl, phenyl or naphthyl, said alkyl, alkenyl, phenyl, naphthyl, and the alkyl portions of xe2x80x94OC1-6alkyl and xe2x80x94SC1-6alkyl being optionally substituted with 1-3 groups selected from halo, OH, CH3O, CF3 and OCF3; and
when taken together,
A and B together represents (a) A1-4alkylene optionally substituted with 1-3 halo groups, and 1-2 Ra groups wherein Ra represents C1-3alkyl, OC1-3alkyl, C6-10arC1-6alkylene or phenyl optionally substituted with 1-3 halo groups, or (b) C2-5alkanediyl such that they form a 3-6 membered ring with the carbon atom to which they are attached, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring being optionally substituted with C1-4alkylene, oxo, ethylenedioxy or propylenedioxy, and being further optionally substituted with 1-4 groups selected from halo, C1-4alkyl, haloC1-4alkyl, C1-3acyl, C1-3acyloxy, C1-3alkoxy, C1-6alkylOC(O)xe2x80x94, C2-4alkenyl, C2-4alkynyl, C1-3alkoxyC1-3alkyl, C1-3alkoxyC1-3alkoxy, phenyl, CN, OH, D, NH2, NHRa and N(Ra)2 wherein Ra is as previously defined;
each R1 represents H or is independently selected from the group consisting of: OH, halo, C1-10alkyl, C1-6alkoxy and C6-10aryl, said C1-10alkyl, C6-10aryl and the alkyl portion of C1-6alkoxy being optionally substituted with 1-3 halo, OH, OC1-3alkyl, phenyl or naphthyl groups, said phenyl and naphthyl being optionally substituted with 1-3 substituents independently selected from halo, OCH3, OCF3, CH3, CF3 and phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,
or two R1 groups taken together represent a fused C5-6alkyl or aryl ring, which may be optionally substituted with 1-2 OH or Ra groups, wherein Ra is as defined above;
R2 and R3 are taken together or separately;
when taken together, R2 and R3 represent (a) a C3-8 alkanediyl forming a fused 5-10 membered non-aromatic ring optionally interrupted with 1-2 double bonds, and optionally interrupted by 1-2 heteroatoms selected from O, S and N; or (b) a fused 6-10 membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic group being optionally substituted with 1-6 halo atoms, and 1-4 of OH, C1-3alkyl, OC1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, C1-3alkyl, OC1-3alkyl, and said C1-3alkyl and the C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups;
when taken separately,
R2 is selected from the group consisting of: (a) C1-14alkyl optionally substituted with 1-6 halo groups and 1-3 substituents selected from OH, OC1-3alkyl, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, OCH3, OCF3, CH3 and CF3, and said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (b) phenyl or pyridyl optionally substituted with 1-3 halo, OH or Ra groups, with Ra as previously defined; (c) C2-10 alkenyl, optionally substituted with 1-3 substituents independently selected from halo, OH and OC1-3alkyl, said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (d) CH2CO2H; (e) CH2CO2C1-6alkyl; (f) CH2C(O)NHRa wherein Ra is as previously defined; (g) NH2, NHRa and N(Ra)2 wherein Ra is as previously defined;
and R3 is selected from the group consisting of: C1-14alkyl, C2-10alkenyl, SC1-6alkyl, C6-10aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and the alkyl portion of SC1-6alkyl being optionally substituted with (a) R; (b) 1-6 halo groups and (c) 1-3 groups selected from OH, NH2, NHC1-4alkyl, N(C1-4alkyl)2, C1-4alkyl, OC1-4alkyl, CN, C1-4alkylS(O)xxe2x80x94 wherein x is 0, 1 or 2, C1-4alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94 and (C1-4alkyl)2NSO2xe2x80x94, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with phenyl and 1-3 halo groups, and
R is selected from heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1-4 groups selected from halo, C1-4alkyl, C1-4alkylS(O)xxe2x80x94, with x as previously defined, C1-4 alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4 alkyl)2NSO2xe2x80x94, CN, OH, OC1-4alkyl, and, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with 1-5 halo and 1 group selected from OH and OC1-3alkyl.
The present invention relates to a compound represented by Formula I: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
A and B may be taken separately or together;
when taken separately,
A represents halo, C1-6alkyl, OC1-6alkyl or phenyl, said alkyl, phenyl and the alkyl portion of OC1-6alkyl being optionally substituted with 1-3 halo groups; and
B represents represents H, halo, C1-6alkyl, xe2x80x94OC1-6alkyl, xe2x80x94SC1-6alkyl, C2-6alkenyl, phenyl or naphthyl, said alkyl, alkenyl, phenyl, naphthyl, and the alkyl portions of xe2x80x94OC1-6alkyl and xe2x80x94SC1-6alkyl being optionally substituted with 1-3 groups selected from halo, OH, CH3O, CF3 and OCF3; and
when taken together,
A and B together represents (a) C1-4alkylene optionally substituted with 1-3 halo groups, and 1-2 Ra groups wherein Ra represents C1-3alkyl, OC1-3alkyl, C6-10arC1-6alkylene or phenyl optionally substituted with 1-3 halo groups, or (b) C2-5alkanediyl such that a 3-6 membered ring is formed with the carbon atom to which they are attached, said ring being optionally interrupted with 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring being optionally substituted with C1-4alkylene, oxo, ethylenedioxy or propylenedioxy, and being further optionally substituted with 1-4 groups selected from halo, C1-4alkyl, haloC1-4alkyl, C1-3acyl, C1-3acyloxy, C1-3alkoxy, C1-6alkylOC(O)xe2x80x94, C2-4alkenyl, C2-4alkynyl, C1-3alkoxyC1-3alkyl, C1-3alkoxyC1-3alkoxy, phenyl, CN, OH, D, NH2, NHRa and N(Ra)2 wherein Ra is as previously defined;
each R1 represents H or is independently selected from the group consisting of: OH, halo, C1-10alkyl, C1-6alkoxy and C6-10aryl, said C1-10alkyl, C6-10aryl and the alkyl portion of C1-6alkoxy being optionally substituted with 1-3 halo, OH, OC1-3alkyl, phenyl or naphthyl groups, said phenyl and naphthyl being optionally substituted with 1-3 substituents independently selected from halo, OCH3, OCF3, CH3, CF3 and phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups,
or two R3 groups taken together represent a fused C5-6alkyl or aryl ring, which may be optionally substituted with 1-2 OH or Ra groups, wherein Ra is as defined above;
R2 and R3 are taken together or separately;
when taken together, R2 and R3 represent (a) a C3-8 alkanediyl forming a fused 5-10 membered non-aromatic ring optionally interrupted with 1-2 double bonds, and optionally interrupted by 1-2 heteroatoms selected from O, S and N; or (b) a fused 6-10 membered aromatic monocyclic or bicyclic group, said alkanediyl and aromatic monocyclic or bicyclic group being optionally substituted with 1-6 halo atoms, and 1-4 of OH, C1-3alkyl, OC1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, C1-3alkyl, OC1-3alkyl, and said C1-3alkyl and the C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups;
when taken separately,
R2 is selected from the group consisting of: (a) C1-14alkyl optionally substituted with 1-6 halo groups and 1-3 substituents selected from OH, OC1-3alkyl, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, OCH3, OCF3, CH3 and CF3, and said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (b) phenyl or pyridyl optionally substituted with 1-3 halo, OH or Ra groups, with Ra as previously defined; (c) C2-10 alkenyl, optionally substituted with 1-3 substituents independently selected from halo, OH and OC1-3alkyl, said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (d) CH2CO2H; (e) CH2CO2C1-6alkyl; (f) CH2C(O)NHRa wherein Ra is as previously defined; (g) NH2, NHRa and N(Ra)2 wherein Ra is as previously defined;
and R3 is selected from the group consisting of: C1-14alkyl, C2-10alkenyl, SC1-6alkyl, C6-10aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and the alkyl portion of SC1-6alkyl being optionally substituted with (a) R; (b) 1-6 halo groups and (c) 1-3 groups selected from OH, NH2, NHC1-4alkyl, N(C1-4alkyl)2, C1-4alkyl, OC1-4alkyl, CN, C1-4alkylS(O)xxe2x80x94 wherein x is 0, 1 or 2, C1-4alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94 and (C1-4alkyl)2NSO2xe2x80x94, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with phenyl and 1-3 halo groups, and
R is selected from heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1-4 groups selected from halo, C1-4alkyl, C1-4alkylS(O)xxe2x80x94, with x as previously defined, C1-4 alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4 alkyl)2NSO2xe2x80x94, CN, OH, OC1-4alkyl, and, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with 1-5 halo and 1 group selected from OH and OC1-3alkyl.
As used herein the following definitions are applicable.
xe2x80x9cAcxe2x80x9d is acetyl, which is CH3C(O)xe2x80x94.
xe2x80x9cAlkylxe2x80x9d, as well as other groups having the prefix xe2x80x9calkxe2x80x9d, such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. Where the specified number of carbon atoms permits, e.g., from C3-C10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, C1-6 is intended.
xe2x80x9cAlkenylxe2x80x9d means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. Where the specifice number of carbon atoms permits, e.g., from C5-C10, the term alkenyl also includes cycloalkenyl groups, and combinations of linear, branched and cyclic structures. When no number of carbon atoms is specified, C2-6 is intended
xe2x80x9cAlkynylxe2x80x9d means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
xe2x80x9cAlkanediylxe2x80x9d refers to carbon chains that are bifunctional, such as xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, and the like. Alkanediyl groups are linear or branched, unless otherwise indicated. For comparison, alkyl groups are monofunctional.
xe2x80x9cAlkylenexe2x80x9d as used herein refers to a carbon atom or carbon chain that is attached through a double bond.
xe2x80x9cCycloalkylxe2x80x9d is a subset of alkyl and means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. A cycloalkyl group generally is monocyclic unless stated otherwise. Cycloalkyl groups are saturated unless otherwise defined.
xe2x80x9cArylxe2x80x9d means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls. The most preferred aryl is phenyl.
xe2x80x9cHeterocyclexe2x80x9d and xe2x80x9chetercyclylxe2x80x9d refer to saturated or unsaturated non-romatic rings or ring systems containing at least one heteroatom selected from O, S and N, further including the oxidized forms of sulfur, SO and SO2). Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, teterhydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine and the like.
xe2x80x9cHeteroarylxe2x80x9d means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N, (including SO). Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are not aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl (including S-oxide), quinolyl, indolyl, isoquinolyl, dibenzofuranyl, napthyridyl and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 atoms are included, forming 1-3 rings.
xe2x80x9cHaloxe2x80x9d and xe2x80x9cHalogenxe2x80x9d refer to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted on an alkyl or alkoxy group (e.g. CF3O and CF3CH2O).
The term xe2x80x9cpharmaceutical compositionxe2x80x9d encompasses a product comprising the active ingredient(s) and a carrier, as well as any product which results, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from a dissociation or another type of reaction of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include those made by admixing a compound or compounds of the present invention and a pharmaceutically acceptable carrier.
Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms are included.
Some of the compounds described herein contain olefinic double bonds. Both E and Z geometric isomers are included in pure form as well as in admixture.
Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are included.
If desired, racemic mixtures of compounds of Formula I may be separated so that individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds of Formula I to an enantiomerically pure compound to form a diastereomeric mixture, which is then separated into individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to substantially pure enantiomers by cleaving the added chiral residue from the diastereomeric compound.
The racemic mixture of the compounds of Formula I can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
Alternatively, enantiomers of compounds of the general Formula I may be obtained by stereoselective synthesis using optically pure starting materials or reagents.
One aspect of the invention that is of particular interest relates to a compound of formula I wherein A and B are taken together and represent C2-5alkanediyl such that a 3-6 membered ring is formed with the carbon atom to which they are attached, said ring optionally containing 1 double bond or 1-2 heteroatoms selected from O, S and N, said 3-6 membered ring being optionally substituted with C1-4alkylene, oxo, ethylenedioxy or propylenedioxy, and being further optionally substituted with 1-4 groups selected from halo, C1-4alkyl, haloC1-4alkyl, C1-3acyl, C1-3acyloxy, C1-3alkoxy, C1-6alkylOC(O)xe2x80x94, C2-4alkenyl, C2-4alkynyl, C1-3alkoxyC1-3alkyl, C1-3alkoxyC1-3alkoxy, phenyl, CN, OH, D, NH2, NHRa and N(Ra)2 wherein Ra represents C1-3alkyl, OC1-3alkyl, C6-10arC1-6alkylene or phenyl optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as defined with respect to formula I.
Another aspect of the invention that is of more particular interest is a compound as described above wherein A and B are taken together and represent a C2-4 membered alkanediyl group such that a 3 to 5 membered ring is formed with the carbon atom to which they are attached, optionally substituted with 1-2 groups selected from halo, C1-4alkyl, haloC1-4alkyl, C1-3alkoxy, C1-3alkoxyC1-3alkyl, C1-3alkoxyC1-3alkoxy and phenyl. Within this aspect of the invention, all other variables are as defined with respect to formula I.
Even more particularly, an aspect of the invention that is of interest relates to a compound as described above wherein A and B are taken together and represent a C2-4 alkanediyl group such that a 3-5 membered ring is formed with the carbon atom to which they are attached, said ring being unsubstituted or substituted with 1-2 halo groups. Within this aspect of the invention, all other variables are as defined with respect to formula I.
Even more particularly, an aspect of the invention that is of interest relates to a compound as described above wherein the 1-2 halo groups are fluoro groups. Within this aspect of the invention, all other variables are as defined with respect to formula I.
In another aspect of the invention that is of interest, a compound of formula I is disclosed wherein two R1 groups represent H and one R1 is selected from the group consisting of: OH, halo, C1-10alkyl, C1-6alkoxy and C6-10aryl, said C1-10alkyl, C6-10aryl and the alkyl portion of C1-6alkoxy being optionally substituted with 1-3 halo, OH, OC1-3alkyl, phenyl or naphthyl groups, said phenyl and naphthyl being optionally substituted with 1-3 substituents selected from: halo, OCH3, OCF3, CH3, CF3 and phenyl, wherein said phenyl is optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as defined with respect to formula I.
More particularly, an aspect of the invention that is of interest relates to a compound of formula I wherein one R1 group represents H and two R1 groups are selected from the group consisting of: OH, halo, C1-10alkyl and C1-6alkoxy, said C1-10alkyl and the alkyl portion of C1-6alkoxy being optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as defined with respect to formula I.
Even more particularly, an aspect of the invention that is of interest relates to a compound of formula I wherein two R1 groups represent halo or methyl. Within this aspect of the invention, all other variables are as defined with respect to formula I.
In another aspect of the invention, a compound of formula I is disclosed wherein R2 is taken separately from R3 and is selected from the group consisting of: (a) C1-14alkyl optionally substituted with 1-6 halo groups and 1-3 substituents selected from OH, OC1-3alkyl, and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, OCH3, OCF3, CH3 and CF3, and said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (b) phenyl or pyridyl optionally substituted with 1-3 halo, OH or Ra groups; (c) C2-10 alkenyl, optionally substituted with 1-3 substituents independently selected from halo, OH and OC1-3alkyl, said C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups; (d) CH2CO2H; (e) CH2CO2C1-6alkyl; (f) CH2C(O)NHRa and (g) NH2, NHRa and N(Ra)2, and
Ra represents C1-3alkyl, OC1-3alkyl, C6-10arC1-6alkylene or phenyl optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
More particularly, an aspect of the invention is disclosed wherein R2 is taken separately from R3 and is C1-14alkyl optionally substituted with 1-6 halo groups and 1-3 substituents selected from OH, OC1-3alkyl and phenyl, said phenyl being optionally substituted with 1-4 groups independently selected from halo, OCH3, OCF3, CH3 and CF3, and the alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Even more particularly, an aspect of the invention that is of particular interest relates to a compound of formula I wherein R2 is taken separately from R3 and represents methyl or cyclopropyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
In a different aspect of the invention, a compound that is of interest is defined in accordance with formula I wherein R3 is taken separately from R2 and is selected from the group consisting of: C1-14alkyl, C2-10alkenyl, SC1-6alkyl, C6-10aryl, heterocyclyl and heteroaryl, said alkyl, alkenyl, aryl, heterocyclyl, heteroaryl and the alkyl portion of SC1-6alkyl being optionally substituted with (a) R; (b) 1-6 halo groups and (c) 1-3 groups selected from OH, NH2, NHC1-4alkyl, N(C1-4alkyl)2, C1-4alkyl, OC1-4alkyl, CN, C1-4alkylS(O)xxe2x80x94 wherein x is 0, 1 or 2, C1-4alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94 and (C1-4alkyl)2NSO2xe2x80x94, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with phenyl and 1-3 halo groups, and
R is selected from heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1-4 groups selected from halo, C1-4alkyl, C1-4alkylS(O)xxe2x80x94, with x as previously defined, C1-4 alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4 alkyl)2xe2x80x94, CN, OH, OC1-4alkyl, and, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with 1-5 halo and 1 group selected from OH and OC1-3alkyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
More particularly, a compound that is of interest is defined in accordance with formula I wherein R3 is taken separately from R2 and is selected from the group consisting of: C1-14alkyl, C6-10aryl, heterocyclyl and heteroaryl, said groups being optionally substituted with (a) R; (b) 1-6 halo groups and (c) 1-3 groups selected from OH, NH2, NHC1-4alkyl, N(C1-4alkyl)2, C1-4alkyl, OC1-4alkyl, CN, C1-4alkylS(O)xxe2x80x94 wherein x is 0, 1 or 2, C1-4alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with phenyl and 1-3 halo groups. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Even more particularly, a compound that is of interest is defined in accordance with formula I wherein R3 is taken separately and is selected from the group consisting of: cyclopropyl optionally substituted with methyl or phenyl; phenyl optionally substituted with halo, OH, OCH3 or OCF3; heteroaryl selected from benzimidazolyl, indolyl, benzofuranyl, and dihydrobenzofuranyl, said heteroaryl groups being optionally substituted with: (a) R; (b) 1-6 halo groups or (c) 1-3 groups selected from OH, NH2, NHC1-4alkyl, N(C1-4alkyl)2, C1-4alkyl, OC1-4alkyl, CN, C1-4alkylS(O)xxe2x80x94 wherein x is 0, 1 or 2, C1-4alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with phenyl and 1-3 halo groups, and
R is selected from heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1-4 groups selected from halo, C1-4alkyl, OH, OC1-4alkyl, and, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with 1-5 halo groups and 1 group selected from OH and OC1-3alkyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
In a different aspect of the invention that is of interest, a compound of formula I is described wherein R1 and R3 are taken together and represent: (a) a C3-8 alkanediyl forming a fused 5-10 membered non-aromatic ring optionally interrupted with 1 double bond, and optionally interrupted by 1 heteroatom selected from O, S and N; or (b) a fused 6-10 membered aromatic monocyclic or bicyclic group,
said alkanediyl and aromatic monocyclic or bicyclic group being optionally substituted with 1-3 halo atoms, and 1-2 of OH, C1-3alkyl, OC1-3alkyl, haloC1-3alkyl, haloC1-3alkoxy and phenyl, said phenyl being optionally substituted with 1-2 groups independently selected from halo, C1-3alkyl, OC1-3alkyl, and said C1-3alkyl and the C1-3alkyl portion of OC1-3alkyl being optionally substituted with 1-3 halo groups. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
More particularly, an aspect of the invention that is of interest relates to a compound of formula I wherein R is selected from heterocyclyl, heteroaryl and aryl, said group being optionally substituted with 1-4 halo groups and 1-2 groups selected from C1-4alkyl, C1-4alkylS(O)xxe2x80x94, wherein x is 0, 1 or 2, C1-4 alkylSO2NHxe2x80x94, H2NSO2xe2x80x94, C1-4alkylNHSO2xe2x80x94, (C1-4alkyl)2NSO2xe2x80x94, CN, OH and OC1-4alkyl, said C1-4alkyl and the C1-4alkyl portions of said groups being optionally substituted with 1-3 halo groups and 1 group selected from OH and OC1-3alkyl. Within this aspect of the invention, all other variables are as originally defined with respect to formula I.
Species falling within the scope of the invention include those disclosed in the examples. A compound that is of particular interest is defined as having the structural formula: 
as well as pharmaceutically acceptable salts and solvates thereof.
Another compound that is of particular interest is defined as having the structural formula: 
as well as pharmaceutically acceptable salts and solvates thereof.
Yet another compound that is of particular interest is defined as having the structural formula: 
as well as pharmaceutically acceptable salts and solvates thereof.
In a different aspect of the invention, a pharmaceutical composition is addressed comprising a compound in accordance with formula I or a salt or hydrate thereof, in combination with a pharmaceutically acceptable carrier.
In another aspect of the invention, a method of treating hyperglycemia, diabetes or insulin resistance in a mammalian patient in need of such treatment is addressed, which comprises administering to said patient an effective amount of a compound in accordance with formula I or a salt or solvate thereof.
In another aspect of the invention, a method of treating non-insulin dependent diabetes mellitus is disclosed in a mammalian patient in need of such treatment comprising administering to the patient an anti-diabetic effective amount of a compound in accordance with formula I.
In another aspect of the invention, a method of treating obesity in a mammalian patient in need of such treatment is disclosed comprising administering to said patient a compound in accordance with formula I in an amount that is effective to treat obesity.
In another aspect of the invention, a method of treating Syndrome X in a mammalian patient in need of such treatment is disclosed, comprising administering to said patient a compound in accordance with formula I in an amount that is effective to treat Syndrome X.
In another aspect of the invention, a method of treating a lipid disorder selected from the group conisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL and high LDL in a mammalian patient in need of such treatment is disclosed, comprising administering to said patient a compound in accordance with formula I in an amount that is effective to treat said lipid disorder.
In another aspect of the invention, a method of treating atherosclerosis in a mammalian patient in need of such treatment is disclosed, comprising administering to said patient a compound in accordance with formula I in an amount effective to treat atherosclerosis.
In another aspect of the invention, a method of treating a condition selected from the group consisting of: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalina patient in need of such treatment is disclosed, comprising administering to the patient a compound in accordance with formula I in an amount that is effective to treat said condition.
In another aspect of the invention, a method of delaying the onset of a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, 7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalina patient in need of such treatment is disclosed, comprising administering to the patient a compound in accordance with formula I in an amount that is effective to delay the onset of said condition.
In another aspect of the invention, a method of reducing the risk of developing a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient a compound in accordance with formula I in an amount that is effective to reduce the risk of developing said condition.
In another aspect of the invention, a method of treating a condition selected from the group consisting of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other conditions and disorders where insulin resistance is a component, in a mammalian patient in need of such treatment, comprising administering to the patient an effective amount of a compound as defined in formula I and a compound selected from the group consisting of:
(a) DP-IV inhibitors;
(b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides;
(c) insulin and insulin mimetics;
(d) sulfonylureas and other insulin secretagogues;
(e) (xcex1-glucosidase inhibitors;
(f) glucagon receptor antagonists;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
(h) GIP,GIP mimetics, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;
(j) cholesterol lowering agents selected from the group consisting of
(i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid and salts thereof, (iv) PPARxcex1 agonists, (v) PPARxcex1/xcex3 dual agonists, (vi) inhibitors of cholesterol absorption,
(vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
(k) PPAR xcex4 agonists;
(l) antiobesity compounds;
(m) an ileal bile acid transporter inhibitor
(n) anti-inflammatory agents excluding glucocorticoids; and
(o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors,
said compounds being administered to the patient in an amount that is effective to treat said condition.
In another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, comprising administering to the patient a therapeutically effective amount of a compound as defined in formula I and an HMG-CoA reductase inhibitor.
More particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, in another aspect of the invention, a method of treating a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, in a mammalian patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
In another aspect of the invention, a method of reducing the risk of developing a condition selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia and dyslipidemia, and the sequelae of such conditions is disclosed comprising administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound as defined in formula I and an HMG-CoA reductase inhibitor.
In another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed comprising administering to said patient an effective amount of a compound as defined in formula I and an HMG-CoA reductase inhibitor.
More particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-CoA reductase inhibitor is a statin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin selected from the group consisting of: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.
Even more particularly, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the statin is simvastatin.
In another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and further comprising administering a cholesterol absorption inhibitor.
More particularly, in another aspect of the invention, a method for delaying the onset or reducing the risk of developing atherosclerosis in a human patient in need of such treatment is disclosed, wherein the HMG-Co A reductase inhibitor is a statin and the cholesterol absorption inhibitor is ezetimibe.
In another aspect of the invention, a pharmaceutical composition is disclosed which comprises
(1) a compound according to formula I,
(2) a compound selected from the group consisting of:
(a) DP-IV inhibitors;
(b) insulin sensitizers selected from the group consisting of (i) PPAR agonists and (ii) biguanides;
(c) insulin and insulin mimetics;
(d) sulfonylureas and other insulin secretagogues;
(e) xcex1-glucosidase inhibitors;
(f) glucagon receptor antagonists;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;
(h) GIP, GIP mimetics, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;
(j) cholesterol lowering agents selected from the group consisting of (i) HMG-CoA reductase inhibitors, (ii) sequestrants, (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARxcex1 agonists, (v) PPARxcex1/xcex3 dual agonists, (vi) inhibitors of cholesterol absorption, (vii) acyl CoA:cholesterol acyltransferase inhibitors, and (viii) anti-oxidants;
(k) PPAR xcex4 agonists;
(l) antiobesity compounds;
(m) an ileal bile acid transporter inhibitor;
(n) anti-inflammatory agents other than glucocorticoids; and
(o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors; and
(3) a pharmaceutically acceptable carrier.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts prepared from pharmaceutically acceptable bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates and polyhydrates.
Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred pharamaceutically acceptable acids include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. In most cases, compounds of the present invention are basic because the triazole ring is basic. The triazole compounds of this invention may also be made and handled as non-pharmaceutically acceptable salts (e.g. trifluoroacetate salts) during synthesis before they are used in making pharmaceuticals.
It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
xe2x80x9cSolvates, and in particular, the hydrates of the compounds of formula I are included in the present invention as well.
Metabolites of the compounds of this invention that are therapeutically active and that are also defined by Formula I are also within the scope of this invention. Prodrugs are compounds that are converted to therapeutically active compounds as they are being administered to a patient or after they have been administered to a patient. Prodrugs, which themselves do not have the structures claimed herein, but which are converted to active compounds defined by Formula I during or after administration to a mammalian patient, are prodrugs and are compounds of this invention, as are their active metabolites that are defined by Formula I.
The compounds described herein are selective inhibitors of the 11xcex2-HSD1 enzyme. Thus, the present invention relates to the use of the 11xcex2-HSD1 inhibitor for inhibiting the reductase activity of 11xcex2-hydroxysteroid dehydrogenase, which is responsible for the conversion of cortisone to cortisol. Excess cortisol is associated with numerous disorders, including NIDDM, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compounds decreases the level of cortisol and other 11xcex2-hydroxysteroids in target tissues, thereby reducing the effects of excessive amounts of cortisol and other 11xcex2-hydroxysteroids. Inhibition of 11xcex2-HSD1 can be used to treat and control diseases mediated by abnormally high levels of cortisol and other 11xcex2-hydroxysteroids, such as NIDDM, obesity, hypertension and dyslipidemia.
The present invention includes the use of an 11xcex2-HSD1 inhibitor for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein, as mediated by excess or uncontrolled amounts of cortisol and/or other corticosteroids in a mammalian patient, particularly a human, by the administration of an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. Inhibition of the 11xcex2-HSD1 enzyme limits the conversion of cortisone, which is normally inert, to cortisol, which can cause or contribute to the symptoms of these diseases and conditions if present in excessive amounts.
NIDDM and Hypertension
The compounds of this invention are selective inhibitors of 11xcex2-HSD1 over 11xcex2-HSD2. While the inhibition of 11xcex2-HSD1 is useful for reducing cortisol levels and treating conditions related thereto, inhibition of 11xcex2-HSD2 is associated with serious side effects, such as hypertension.
Cortisol is an important and well recognized anti-inflammatory hormone, which also acts as an antagonist to the action of insulin in the liver, such that insulin sensitivity is reduced, resulting in increased gluconeogenesis and elevated levels of glucose in the liver. Patients who already have impaired glucose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of cortisol.
High levels of cortisol in tissues where the mineralocorticoid receptor is present often lead to hypertension. Inhibition of 11xcex2-HSD1 shifts the ratio of cortisol and cortisone in specific tissues in favor of cortisone.
Administration of a therapeutically effective amount of an 11xcex2-HSD1 inhibitor is effective in treating, controlling and ameliorating the symptoms NIDDM, and administration of a therapeutically effective amount of an 11xcex2-HSD1 inhibitor on a regular basis delays or prevents the onset of NIDDM, particularly in humans.
Cushing""s Syndrome
The effect of elevated levels of cortisol is also observed in patients who have Cushing""s syndrome, which is a metabolic disease characterized by high levels of cortisol in the blood stream. Patients with Cushing""s syndrome often develop NIDDM.
Obesity, Metabolic Syndrome, Dyslipidemia
Excessive levels of cortisol have been associated with obesity, perhaps due to increased hepatic gluconeogenesis. Abdominal obesity is closely associated with glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and other factors of Syndrome X, such as high blood pressure, elevated VLDL and reduced HDL. Montague et al., Diabetes, 2000, 49: 883-888. Thus, the administration of an effective amount of an 11xcex2-HSD1 inhibitor is useful in the treatment or control of obesity. Long-term treatment with an 11xcex2-HSD1 inhibitor is also useful in delaying or preventing the onset of obesity, especially if the patient uses an 11xcex2-HSD1 inhibitor in combination with controlled diet and exercise.
By reducing insulin resistance and maintaining serum glucose at normal concentrations, compounds of this invention also have utility in the treatment and prevention of conditions that accompany Type II diabetes and insulin resistance, including the metabolic syndrome (xe2x80x9cSyndrome Xxe2x80x9d), obesity, reactive hypoglycemia and diabetic dyslipidemia.
Cognition and Dementia
Excessive levels of cortisol in the brain may also result in neuronal loss or dysfunction through the potentiation of neurotoxins. Cognitive impairment has been associated with aging, and excess levels of cortisol in the brain. See J. R. Seckl and B. R. Walker, Endocrinology, 2001, 142: 1371-1376, and references cited therein. Administration of an effective amount of an 11xcex2-HSD1 inhibitor results in the reduction, amelioration, control or prevention of cognitive impairment associated with aging and of neuronal dysfunction.
Atherosclerosis
As described above, inhibition of 11xcex2-HSD1 activity and a reduction in the amount of cortisol are beneficial in treating or controlling hypertension. Since hypertension and dyslipidemia contribute to the development of atherosclerosis, administration of a therapeutically effective amount of an 11xcex2-HSD1 inhibitor of this invention may be especially beneficial in treating, controlling, delaying the onset of or preventing atherosclerosis.
Effects on Pancreas
Inhibition of 11xcex2-HSD1 activity in isolated murine pancreatic xcex2-cells improves glucose stimulated insulin secretion (B. Davani et al., J. Biol. Chem., 2000, 275: 34841-34844). Glucocorticoids have been shown to reduce insulin secretion in vivo. (B. Billaudel et al., Horm. Metab. Res., 1979, 11: 555-560).
Reduction of Intraocular Pressure
Recent data suggests a connection between the levels of glucocorticoid target receptors and the 11xcex2-HSD enzymes and thesusceptibility to glaucoma (J. Stokes et al., Invest. Ophthamol., 2000, 41: 1629-1638). Therefore, inhibition of 11xcex2-HSD1 activity is useful in reducing intraocular pressure in the treatment of glaucoma.
Immunomodulation
In certain disease states, such as tuberculosis, psoriasis, and even under conditions of excessive stress, high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to the patient. Inhibition of 11xcex2-HSD1 activity and the attendant reduction in glucocorticoid levels shifts the immune response toward a cell based response. See D. Mason, Immunology Today, 1991, 12: 57-60, and G. A. W. Rook, Baillixc3xa8r""s Clin,Endocrinol. Metab., 1999, 13: 576-581.
Osteoporosis
Glucocorticoids can inhibit bone formation, which can result in a net bone loss. 11xcex2-HSD1 has a role in bone resorption. Inhibition of 11xcex2-HSD1 is beneficial in preventing bone loss due to osteoporosis. See C. H. Kim et al., J. Endocrinol., 1999, 162: 371-379; C. G. Bellows et al., Bone, 1998,23: 119-125; and M. S. Cooper et al., Bone, 2000, 27: 375-381.
Other Utilities
The following diseases, disorders and conditions can be treated, controlled, prevented or delayed, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) pancreatitis, (15) abdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropathy, (19) neuropathy, (20) Syndrome X, and other disorders where insulin resistance is a component.
The above diseases and conditions can be treated using the compounds of formula I, or the compound can be administered to prevent or reduce the risk of developintg the diseases and conditions described herein. Since concurrent inhibition of 11xcex2-HSD2 may have deleterious side effects or may actually increase the amount of cortisol in the target tissue where reduction of cortisol is desired, selective inhibitors of 11xcex2-HSD1 with little or no inhibition of 11xcex2-HSD2 are desirable.
The 11xcex2-HSD1 inhibitors of formula I generally have an inhibition constant IC50 of less than about 500 nM, and preferably less than about 100 nM. Generally, the IC50 ratio for 11xcex2-HSD2 to 11xcex2-HSD1 of a compound is at least about two or more, and preferably about ten or greater. Even more preferred are compounds with an IC50 ratio for 11xcex2-HSD2 to 11xcex2-HSD1 of about 100 or greater. For example, for compounds having an IC50 the compounds ideally demonstrate an inhibition constant IC50 against 11xcex2-HSD2 greater than about 500 nM, and preferably greater than 1000 nM.
Compounds of Formula I may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs have utility. Typically the combination of the drugs is safer or more effective than either drug alone, or the combination is safer or more effective than would be expected based on the additive properties of the individual drugs. Such other drug(s) may be administered, by a route and in an amount commonly used contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a combination product containing such other drug(s) and the compound of Formula I is preferred. However, combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention or the other active ingredient or both may be used effectively in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I.
Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
(a) dipeptidyl peptidase IV (DP-IV) inhibitors;
(b) insulin sensitizers including (i) PPARxcex3 agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, including PPARxcex1/xcex3 dual agonists, such as KRP-297, and PPARxcex1 agonists such as gemfibrozil, clofibrate, fenofibrate and bezafibrate, and (ii) biguanides, such as metformin and phenformin;
(c) insulin or insulin mimetics;
(d) sulfonylureas and other insulin secretagogues such as tolbutamide and glipizide, meglitinide and related materials;
(e) xcex2-glucosidase inhibitors (such as acarbose);
(f) glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088 and WO 00/69810;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as those disclosed in WO00/42026 and WO00/59887;
(h) GIP, GIP mimetics such as those disclosed in WO00/58360, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) inhibitors of cholesterol absorption, such as for example ezetimibe and beta-sitosterol, (v) acyl CoA:cholesterol acyltransferase inhibitors, such as for example avasimibe, and (vi) anti-oxidants such as probucol;
(k) PPARxcex4 agonists, such as those disclosed in WO97/28149;
(l) antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, CB1 receptor inverse agonists and antagonists, and xcex23 adrenergic receptor agonists;
(m) an ileal bile acid transporter inhibitor;
(n) agents intended for use in inflammatory conditions other than glucocorticoids, such as aspirin, non-steroidal anti-inflammatory drugs, azulfidine, and cyclooxygenase 2 selective inhibitors, and
(o) protein tyrosine phosphatase-1B (PTP-1B) inhibitors.
The above combinations include a compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, not only with one or more other active compounds. Non-limiting examples include combinations of compounds of Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, DP-IV inhibitors and anti-obesity compounds.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like. Preferably the compound of Formula I is administered orally.
The effective dosage of the active ingredient varies depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition. Such dosages may be ascertained readily by a person skilled in the art.
When treating or preventing the diseases and conditions described herein, for which compounds of Formula I are indicated, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about about 0.1 to about 100 milligram per kilogram (mpk) of body weight, preferably given as a single daily dose or in divided doses about two to six times a day. The total daily dosage thus ranges from about 0.1 mg.to about 1000 mgs., preferably from about 1 mg. to about 50 mgs. In the case of a typical 70 kg adult human, the total daily dose will range from about 7 mgs. to about 350 mgs. This dosage may be adjusted to provide the optimal therapeutic response.
Another aspect of the present invention relates to a pharmaceutical composition which comprises a compound of Formula I, or a pharmaceutically acceptable salt, hydrate otr solvate thereof, in combination with a pharmaceutically acceptable carrier.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), transdermal, pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
The compound of Formula I can be combined with the pharmaceutical carrier according to conventional pharmaceutical compounding techniques. Carriers take a wide variety of forms. For example, carriers for oral liquid compositions include, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and other components used in the manufacture of oral liquid suspensions, elixirs and solutions. Carriers such as starches, sugars and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like are used to prepare oral solid dosage forms, e.g., powders, hard and soft capsules and tablets. Solid oral preparations are preferred over oral liquids.
The oral solid dosage forms may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. Capsules may also contain a liquid carrier such as a fatty oil.
Various other materials may be present to act as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both.
Tablets may be coated by standard aqueous or nonaqueous techniques. The typical percentage of active compound in these compositions may, of course, be varied from about 2 percent to about 60 percent on a w/w basis. Thus, tablets contain a compound of formula I or a salt or hydrate thereof in an amount ranging from as low as about 0.1 mg to as high as about 1.5 g, preferably from as low as about 1.0 mg to as high as about 500 mg, and more preferably from as low as about 10 mg to as high as about 100 mg.
Oral liquids such as syrups or elixirs may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Parenterals are typically in the form of a solution or suspension, typically prepared with water, and optionally including a surfactant such as hydroxypropylcellulose. Dispersions can be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Typically preparations that are in diluted form also contain a preservative.
The pharmaceutical injectable dosage forms, including aqueous solutions and dispersions and powders for the extemporaneous preparation of injectable solutions or dispersions, are also sterile and must be fluid to the extent that easy syringability exists; they must be stable under the conditions of manufacture and storage and are usually preserved. The carrier thus includes the solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
In vitro enzymatic activity was assessed for test compounds via a Scintillation Proximity Assay (SPA). In short, tritiated-cortisone substrate, NADPH cofactor and titrated compound were incubated with 11xcex2-HSD1 enzyme at 37xc2x0 C. to allow conversion to cortisol to progress. Following this incubation, a preparation of protein A coated SPA beads, pre-blended with anti-cortisol monoclonal antibody and a non-specific 11xcex2-HSD inhibitor, was added to each well. The mixture was shaken at 15xc2x0 C. and was then read on a liquid scintillation counter suitable for 96 well plates. Percent inhibition was calculated relative to a non-inhibited control well and IC50 curves were generated. This assay was similarly applied to 11xcex2-HSD2, whereby tritiated cortisol and NAD were used as the substrate and cofactor, respectively. To begin the assay, 40 xcexcL of substrate (25 nM 3H-Cortisone+1.25 mM NADPH in 50 mM HEPES Buffer, pH 7.4) was added to designated wells on a 96 well plate. Solid compound was dissolved in DMSO at 10 mM followed by a subsequent 50 fold dilution in DMSO. The diluted material was then titrated 4 fold, seven times. 1 xcexcL of each titrated compound was then added in duplicate to the substrate. To start the reaction, 10 xcexcL of 11xcex2-HSD1 microsome from CHO transfectants was added to each well at the appropriate concentration to yield approximately 10% conversion of the starting material. For ultimate calculation of percent inhibition, a series of wells were added that represented the assay minimum and maximum: one set that contained substrate without compound or enzyme (background), and another set that contained substrate and enzyme without any compound (maximum signal). The plates were spun briefly at a low speed in a centrifuge to pool the reagents, sealed with an adhesive strip, mixed gently, and incubated at 37xc2x0 C. for 2 hours. After incubation, 45 xcexcL of SPA beads, pre-suspended with anti-cortisol monoclonal antibody and non-specific 11xcex2-HSD inhibitor, were added to each well. The plates were resealed and shaken gently for greater than 1.5 hours at 15xc2x0 C. Data was collected on a plate based liquid scintillation counter such as a Topcount. To control for inhibition of anti-cortisol antibody/cortisol binding, substrate spiked with 1.25 nM [3]H cortisol was added to designated single wells. 1 xcexcL of 200 xcexcM compound was added to each of these wells, along with 10 xcexcL of buffer instead of enzyme. Any calculated inhibiton was due to compound interfering with the cortisol binding to the antibody on the SPA beads.
In general terms, the test compound was dosed orally to a mammal and a prescribed time interval was allowed to elapse, usually between 1 and 24 hours. Tritiated cortisone was injected intavenously, followed several minutes later by blood collection. Steroids were extracted from the separated serum and analyzed by HPLC. The relative levels of 3H-cortisone and its reduction product, 3H-cortisol, were determined for the compound and vehicle-dosed control groups. The absolute conversion, as well as the percentage of inhibtion, were calculated from these values.
More specifically, compounds were prepared for oral dosing by dissolving them in vehicle (5% hydroxypropyl-beta-cyclodextrin v/v H2O, or equivalent) at the desired concentration to allow dosing at typically 10 milligrams per kilogram. Following an overnight fasting, the solutions were dosed to ICR mice (obtained from Charles River) by oral gavage, 0.5 mL per dose per animal, with three animals per test group.
After the desired time had passed, routinely either 1 or 4 hours, 0.2 mL of 3 xcexcM 3H-cortisone in dPBS was injected by tail vein. The animal was caged for two minutes followed by euthanasia in a CO2 chamber. Upon expiration, the mouse was removed and blood was collected by cardiac puncture. The blood was set aside in a serum separation tube for no less than 30 minutes at room temperature to allow for adequate coagulation. After the incubation period, blood was separated into serum by centrifugation at 300xc3x97g, 4xc2x0 C., for 10 minutes.
To analyze the steroids in the serum they were first extracted with organic solvent. A 0.2 mL volume of serum was transferred to a clean microcentrifuge tube. To this a 1.0 mL volume of ethyl acetate was added, followed by vigorous vortexing for 1 minute. A quick spin on a microcentrifuge pelleted the aqueous serum proteins and clarified the organic supernatant. 0.85 mL of the upper organic phase was transferred to a fresh microcentrifuge tube and dried. The dried sample was resuspended in 0.250 mL of DMSO containing a high concentration of cortisone and cortisol for analysis by HPLC.
A 0.200 mL sample was injected onto a Metachem Inertsil C-18 chromatography column equilibrated in 30% methanol. A slow linear gradient to 50% methanol separated the target steroids; simultaneous monitoring by UV at 254 nM of the cold standards in the resuspension solution acted as an internal standard. The tritium signal was collected by a radiochromatography detector that uploaded data to software for analysis. The percent conversion of 3H-cortisone to 3H-cortisol was calculated as the ratio of AUC for cortisol over the combined AUC for cortisone and cortisol.